Synthesis of 8-[18F]fluoroguanine derivatives: in vivo probes for imaging gene expression with positron emission tomography☆
Introduction
Gene therapy based treatment of cancer related diseases is a novel and useful concept. In this strategy, tumor cells are selectively targeted and destroyed through the delivery and expression of foreign genes into malignant cells. These contrived genes convert relatively nontoxic prodrugs into metabolites that are toxic to the malignant cells. A typical example of this methodology is the gene therapy approach with herpes simplex virus type-1 thymidine kinase gene (HSV1-tk), one of the most widely used systems in tumor models (9). The HSV1-tk gene expresses high levels of the enzyme thymidine kinase (HSV1-TK), which monophosphorylates acycloguanosines 8, 11, 25. The acycloguanosine monophosphates are subsequently converted to their corresponding triphosphates by the host endogenous cellular kinases 8, 18, 26. Incorporation of the acycloguanosine triphosphate into the host DNA induces chain termination and cell death 8, 11. At the tracer level, this methodology based on the HSV1-tk gene mediated expression of the phosphorylating enzyme (HSV1-TK) allows the in vivo determination of the gene expression, as recently exemplified with the use of 3H, 14C, and 18F-labeled acyclovir, ganciclovir, and penciclovir 6, 13, 14, 15. Radioiodine labeled pyrimidine nucleosides 20, 21, 27, 28, 29 as well as purine nucleosides labeled with 18F in the acyclochain 1, 2, 19 have recently been prepared and successfully utilized in studies related to HSV1-tk gene expression, attesting to the interest in this new and rapidly developing field 13, 22. The utility of acycloguanosines as probes for imaging gene expression is based on three appealing attributes: 1) very low phosphorylation rates by mammalian thymidine kinase 3, 10, 2) excellent in vivo stability 12, 23, and 3) low host toxicity 10, 12, 23.
Based on a new approach developed in our laboratories for a selective C-8 fluorination of purines with elemental fluorine 4, 5, 6 we have now extended this procedure for the synthesis of 8-[18F]fluoroacycloguanosines. Described in this article are the synthesis of 8-[18F]fluoroganciclovir, 8-[18F]fluoropenciclovir, 8-[18F]fluoroacyclovir, and 8-[18F]fluoroguanosine as examples of a general method for the synthesis of 8-[18F]fluoroguanine derivatives.
Section snippets
General
The 1H and 19F nuclear magnetic resonance (NMR) spectra were recorded on a Bruker (Billerica, MA USA) AM-360 WB spectrometer. The 13C NMR data were collected on a Bruker ARX-500 spectrometer. The 1H and 13C chemical shifts were referenced to internal tetramethylsilane (TMS), whereas the 19F chemical shifts were referenced to an external fluorotrichloromethane standard. Fast atom bombardment (FAB) and electron impact (EI) high-resolution mass spectra (HRMS) were obtained on a ZAB SE mass
Results and discussion
A simple and regioselective procedure for fluorination of purine nucleosides at carbon-8 with elemental fluorine has recently been reported from our laboratories 4, 5, 6. This technique has been extended, in this report, to the synthesis of 8-fluoro-9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (2a, 8-fluoroganciclovir), 8-fluoro-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (2b, 8-fluoropenciclovir), and their corresponding radiolabeled analogs 8-[18F]fluoroganciclovir (3a) and 8-[18
Acknowledgements
We thank the UCLA Biomedical Cyclotron staff for their help.
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Efficient synthesis of 9-(4-[<sup>18</sup>F]fluoro-3-hydroxymethylbutyl)guanine ([<sup>18</sup>F]FHBG) and 9-[(3-[<sup>18</sup>F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([<sup>18</sup>F]FHPG)
2017, Journal of Fluorine ChemistryCitation Excerpt :As a prelude to mapping the thymidine kinase gene using PET, we previously developed a regiospecific fluorination (at carbon-8) method for purines with elemental fluorine [7] and extended that technique to the preparation of the corresponding 8-[18F]fluoro-analogs as reporter probes [8]. Among all the PET reporter probes, [18F]FHBG (4) [9–12], and to a lesser extent [18F]FHPG (6) [13–15], have convincingly become the most useful purine based gene imaging agents for HSV1-tk enzyme and its mutated counterparts HSV1-sr39tk and HSV1-A167Ysr39tk [6,16]. Investigations have also demonstrated that [18F]FHBG is more preferred over [18F]FHPG for imaging gene expression in tumors because of its higher accumulation in transduced cells [6,11].
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This work was supported by Department of Energy contract DE-FC03-87ER60615.